Patients presenting with depression (DEP) and cognitive impairment (CI), DEP-CI, represent a unique, understudied population that is difficult to diagnose, treat and estimate prognosis. Our pilot data, supported by the literature, suggest that many DEP-CI patients show cognitive decline and often convert to dementia, primarily Alzheimer's disease (AD). In DEP-CI, there is a lack of data on treatment response of mood symptoms to antidepressant treatment and particularly of cognitive deficits to cognitive enhancer treatment. Our initial pilot data in a double-blind study showed that donepezil was superior to placebo in improving memory in antidepressant-treated DEP-CI patients. In a second pilot study, open label es-citalopram plus memantine treatment led to a low rate of conversion to dementia. In this proposed pilot clinical trial, we will evaluate, treat and follow a broad sample of 80 DEP-CI patients who present to the departments of Psychiatry, Neurology and Internal Medicine at NYSPI/Columbia University Medical Center and Duke University Medical Center. In the treatment protocol, all 80 DEP-CI patients will receive open antidepressant treatment with citalopram for 4 weeks. At 4 weeks, patients will be randomized to add-on donepezil or placebo. After another 12 weeks (16 weeks into the trial), patients will receive in addition add-on memantine for the donepezil cell and add-on placebo for the placebo cell, i.e., (donepezil + memantine) versus (placebo + placebo). Patients will be followed for a total period of 18 months with continuous open antidepressant treatment during the trial. We chose to study donepezil plus memantine compared to placebo based on our pilot data and to increase the likelihood of obtaining a signal. If the results are positive (reduction in conversion to dementia and better cognitive outcome compared to placebo), whether the effect is due to donepezil or memantine or their combination can be clarified in subsequent trials. Apolipoprotein E e4 genotype, odor identification deficits, and MRI hippocampal and entorhinal cortex atrophy will be explored as predictors of donepezil/memantine response in the 18-month trial. Improving cognition and delaying conversion to a clinical diagnosis of dementia in this high risk group will enhance quality of life, reduce family burden, and markedly diminish overall health care costs. Based on the results, future cognitive enhancer treatment trials for MCI and AD may need to consider including patients with comorbid depression. The study will also provide important information on neurobiological moderators of treatment response and course in DEP-CI. PUBLIC HEALTH RELEVANCE: Depression and cognitive disorders are the most common neuropsychiatric disorders in the elderly. Nearly all treatment studies have focused on patients with late-life depression or MCI or dementia, with little data on treatment of DEP-CI. This study examines treatment of these patients with antidepressants plus either a combination of donepezil and memantine or placebo in order to compare risk of conversion to dementia and cognitive decline. The study has major public health implications because improving cognition and, in particular, delaying conversion to dementia in the high risk DEP-CI group will improve quality of life, reduce family burden, and diminish health care costs. Further, cognitive enhancer treatment trials for MCI and AD may need to consider including patients with comorbid depression. This study will provide critical information to develop personalized treatment for patients with DEP-CI.